Dr Arzoo Nephrology Theses

Renal Impairment due to Intravenous Drug Addiction: A Case Report

By Dr Azam Arzoo M.B.B.S ( Bangladesh) Dissertation for the award of (MMed Sci) in Nephrology Sheffield Kidney Institute University of Sheffield

Supervisor Professor A M El Nahas Professor of Nephrology, University of Sheffield Sheffield Kidney Institute, Northern General Hospital Sheffield - United Kingdom September 2007 1    

CONTENTS 

 

PAGES 

 

List of abbreviations  

 

03‐04 

 

List of table 

 

 

Table ‐1 

Findings of Blood Tests for Specific Types of Acute Kidney Injury

11 

Table ‐2 

Findings on Urinalysis in the Broad Categories of Acute Kidney Injury 

13 

Table ‐3 

Diagnostic Indices in Acute Kidney Injury

17 

Table ‐4 

Differential Diagnosis of Acute Kidney Injury

18 

Table‐5 

Supportive therapies for renal dysfunction 

24 

List of figure 

 

 

Figure‐1 

Diagnosis and treatment of acute renal failure. 

16 

 

Acknowledgement 

 

05 

 

 Dedication 

 

06 

 

 Abstract 

 

07 

 

Chapter‐I 

 

 

 

Introduction   

Chapter‐II 

07‐09   

Clinical approach   

 

Chapter‐III 

  09‐16 

 

 

Differential diagnosis 

17‐24 

Literature review

19‐24 

Management 

24‐25 

Chapter‐IV 

 

 

Discussion 

26‐29 

Conclusion 

29 

References 

30‐35 

2    

List of abbreviations AA:

Amyloid A

ACE:

Angiotensin-converting enzyme

ACEi:

Angiotensin Converting Enzyme Inhibitor

AIN:

Acute interstitial nephritis

AKI:

Acute Kidney Injury

ARB:

Angiotensin Receptor Blocker

ART:

Antiretroviral therapy

ATN:

Acute Tubular Necrosis

BP:

Blood Pressure

CAPD:

Continious Ambulatory Peritoneal Dialysis

CKD:

Chronic Kidney Disease

EM:

Electron microscopy

ESRD:

End-stage renal disease

ESRD:

End stage of Renal Disease

FSGS:

Focal segmental glomerulosclerosis

GFR:

Glomerular filtration rate

GFR:

Glomerular filtration Rate

GN:

Glomerulonephritis

GN:

Glomerulonephritis

HD:

Haemodialysis

HIV:

Human immunodeficiency virus

HSP:

Henoch-Schönlein purpura

IC:

Immune complex

IDUs:

injecting drug users 3  

 

IHD:

Ischaemic Heart Disease

MPGN:

Membranoproliferative glomerulonephritis

NGAL:

Neutrophil gelatinase-associated lipocalin

NP:

Nephropathy

NSAID:

Non Steroidal Anti Inflamatory Drug

NSAID:

Nonsteroidal anti-inflammatory agent

PD:

Peritoneal Dialysis

PSGN:

Poststreptococcal glomerulonephritis

RPGN:

Rapidly progressive glomerulonephritis

RRT:

Renal replacement Theraphy

S.Cr:

Serum Creatinine

SKI:

Sheffield Kidney Institute

SLE:

Systemic lupus erythematosus

                   

4    

 

ACKNOWLEDGEMENT

First and foremost, is praised to Almighty ALLAH, the creator of the world, the beneficent and the most merciful. Without his help and guidance, this work, and every other work, would not be possible

My sincerest appreciation to Prof AM EL NAHAS, for affording me the opportunity to pursue this thesis in the department of Nephrology, Sheffield Kidney Institute, University of Sheffield and for his guidance and supervision all through the preparation of this thesis.

I would like to thank Dr Lutfi, Dr Kossi, Dr Brown, Dr Brenann, Dr Kawar, Dr Othman, Dr Parvez, Dr Amino Bello and Dr Ghada Said M. Omar

Finally, my deepest gratitude is due to my parents, brothers and sister for their love, prayer and continues encouragement throughout the course.               5    

Dedicated to

My mother, Late Tasliman Nisa who sacrifices her whole life to make me a doctor and dreamt for me to get specialized degree from England and her wish was that “Before being a good doctor I should be a good human being”

6    

Abstract A 28 year old intravenous drug addict has presented to the Sheffield Kidney Institute with impaired kidney function (serum creatinine 215 umol/l) and heavy proteinuria (4.5 g/24h). Physical examination is normal with the exception of peripheral oedema. The most likely diagnosis is; acute kidney injury as a consequence of the history of drug addiction. The Management approach would be to focus on immediate treatment of the acute kidney injury, however long term drug withdrawal rehabilitation plan has to be addressed.

Chapter I Introduction Drugs are administered through different routes. Injection of the drug directly into the bloodstream (intravenously) is the most dangerous route; this is because the pathogens can be introduced into the body via the blood steam through the contaminated shared needles due to the lack of sterile preparation and injection techniques. Medical problems may also arise from the damage to body organs caused by the drugs themselves (i.e. the direct effect of the drugs on the body organs due to drug overdose). Another problem could be the impurity of the injected drugs; that may contain some substances such as talc, lactate, or quinine which complicate the condition and might increase the risk of infection (Landry, 1994; Joyce et al., 2005). Drug addicts most commonly use the intravenous route. Prevalence of drug use amongst the adult population in the United Kingdom is estimated to be 53 %. The highest prevalence level for lifetime drug use is now amongst 16 to 34 year olds. In addition, young people aged 16 to 24 years old continue to show the highest levels of recent and current use (Eaton, 2005). The mortality rate for injecting drug users (IDUs) from all causes is estimated to be 3-4% per year (Baciewicz, 2005). Many local and systemic complications are known to be associated with IV drug use, most commonly the transmission of infectious diseases such as hepatitis and human immunodeficiency virus (HIV) via needle sharing. The most commonly injected drugs are heroin 7    

and cocaine. Amphetamines, buprenorphine, benzodiazepines, and barbiturates are also used. It was reported that any water-soluble drug may be injected IV (Baciewicz, 2005). Local complications that are known to be associated with IV administration of drugs include; abscess, cellulitis, septic thrombophlebitis, local induration, necrotizing fascitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (eg, broken needle parts). The most common reported infectious organisms are; Staphylococcus aureus or Staphylococcus epidermidis, streptococci, and gram-negative bacilli. The well reported systemic problems associated with IV drug use in addition to the HIV infection and hepatitis (B or C) mentioned above are; pneumonia and lung abscess from septic emboli to the lung, acute and subacute bacterial endocarditis, group A beta-hemolytic streptococcal septicemia, osteomyelitis, septic arthritis, candidal and other fungal infections, tetanus, clostridial myonecrosis, malaria, and amyloidosis. The endocarditis that occurs in IDUs involves the rightsided heart valves; a recent review found no explanation for this predilection (Frontera and Gradon, 2000). A rare case of needle embolization to the lung has been reported (Baciewicz, 2005).

Furthermore, IV drug abuse may also result in numerous acute and chronic renal consequences. Acute effects include: Oliguria (Goodman & Gilman, 1990), acute renal failure mainly. While chronic effects include: glomerulonephritis of immunological origin, chronic glomerulonephritis with segmental, focal and diffuse glomerulosclerosis, which may lead to terminal renal failure in one to four years (Cunningham et al., 1980). Segmental hyalinosis, nephrotic syndrome and renal amyloid, glomerulonephritis (may be membranous), proliferative or membrano-proliferative Good pasture syndrome have been reported to be associated with IV drug addiction (Uzan et al., 1988; Vassals & Pezzano, 1987). Pyuria and proteinuria are frequently reported (Duberstein & Myland Kaufman, 1971), as well rhabdomyolysis due to a direct effect of drug injection (D'Agostino & Ernest, 1979; Conti et al., 1990). The explanation was given that rhabdomyolysis is due to the compression of muscle during prolonged coma aggravated by hypoxia, acidosis and hypovolemia (Pearce & Cox, 1980; Ellenhorn & Barceloux, 1988,Vassals & Pezzano, 1987; Uzan et al., 1988). Renal damage may progress to terminal renal insufficiency (Cunningham et al., 1980). Genetic factors (African Carribean), and impurities in 8    

the heroin (direct toxicity, or immunogenicity) have been suggested to cause renal insufficiency (Cunningham et al., 1980). There is no experimental evidence concerning the effects of repeated injection of unsterile heroin on renal function. In humans, such injections generally introduce a variety of antigens, and can lead to circulating immune complexes (Uzan et al., 1988).

Chapter II Clinical Approach A 28 year old addict boy admitted to the Northern General Hospital, Sheffield Kidney Institute, with an impaired kidney function following intravenous drug abuse. The patient laboratory results showed increased serum creatinine level of 215 umol/l and heavy proteinuria (4.5 g/24h). All physical examination is normal with the exception of peripheral oedema. The patient showed heavy proteinuria which is strong marker of nephritic syndrome and glomerular disease. On the other hand, serum creatinine is a poor marker of nephrotic syndrome (Branten et al., 2005).

Approach to the Patient with Renal Disease-Associated Proteinuria and elevated serum creatinine Once it has been established that the patient has constant proteinuria, regardless of position and functional status, a careful evaluation is needed, starting with a detailed history and physical examination. The history should identify the presence of pre-existing systemic diseases, particularly diabetes mellitus, SLE, hypertension, and certain infections that are associated with glomerular pathology, such as hepatitis, syphilis, or endocarditis. A drug history is also essential. Intravenous drug abuse has been associated with a pattern of renal disease that morphologically resembles but is not identical to focal segmental glomerulosclerosis (Rao et al., 1974). Heavy use of nonsteroidal anti-inflammatory drugs can be associated with prominent rates of proteinuria (Brezin et al., 1979). The presence of a rash or arthritis which suggests a vasculitis or systemic disease should be carefully evaluated. Significant weight loss may be an indication of an occult malignancy, which can be associated with a glomerulopathy. The presence of a family history of familial renal disease, particularly with certain rare structural defects, such as deformities of the nails and patella, are associated with heavy proteinuria (nail-patella syndrome) (Hoyer et al., 9    

1972). In addition, HIV infection may be associated with a form of nephropathy and progressive renal disease (Bourgoignie et al., 1988). During physical examination particular attention should be given to the patient’s blood pressure and retinal findings. Other elements to be considered are the heart size and any unusual skin lesions such as palpable purpura suggestive of vasculitis or interstitial nephritis, periorbital lesions (“racoon’s eyes”) may suggest the presence of amyloid. The funduscopic examination is particularly important because it may reveal early diabetic retinopathy, even in the patient without the diagnosis of diabetes mellitus, however in this case this is unlikely because of the age of the patient. Likewise, the presence of a rash may suggest a drug reaction, SLE, vasculitis, or cryoglobulinemia which may all cause proteinuria. Enlargement of the lymph nodes, hepatosplenomegaly may be a consequence of certain lymphomas, particularly Hodgkin disease, which can be associated with minimal change disease (Dabbs et al., 1986) and membranous glomerulonephritis has been reported to be associated with several different malignancies, including lung and colon cancer (Striker et al., 1985), although a rectal examinations and testing for occult blood in the stool may be valuable, colonoscopy in the evaluation of choice for such malignancies, however in this case may not be necessary due to the unlikely presence of such malignancies that usually associated with older age. Blood and urine tests can provide supporting data. BUN and serum electrolyte, creatinine, calcium, phosphorus and albumin levels, as well as a complete blood count with differential, should be obtained in this patient. The degree of renal function should be determined by measuring serum creatinine or estimation of GFR by e.g. the use of the Cockcroft and Gault formula and 24 hrs of creatinine clearance, this also should include 24 hrs protein urine excretions. The most simple and safe clinical index of renal function is 24 hour urine creatinine clearance, which will approximates glomerular filtration rate. In certain circumstances, other blood tests are indicated (Table 1). All patients should have the following urine studies: dipstick test, microscopy, sodium and creatinine levels, and urine osmolality determination (Agrawal and Swartz, 2000).

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TABLE 1 Findings of Blood Tests for Specific Types of Acute Kidney Injury

Findings on blood tests

Diagnoses to consider

Elevated uric acid level

Suggestive of malignancy or tumor lysis syndrome leading to uric acid crystals; also seen in prerenal acute renal failure

Elevated creatine kinase or myoglobin levels

Rhabdomyolysis

Elevated prostate-specific antigen

Prostate cancer

Abnormal serum protein electrophoresis

Multiple myeloma

Low complement levels

Systemic lupus erythematosus, postinfectious glomerulonephritis, subacute bacterial endocarditis

Positive antineutrophilic cytoplasmic antibody

Small-vessel vasculitis (Wegener's granulomatosis or polyarteritis nodosa)

Positive antinuclear antibody or antibody to double- Systemic lupus erythematosus stranded DNA Positive antibody to glomerular basement membrane

Goodpasture's syndrome

Positive antibodies to streptolysin O, streptokinase Poststreptococcal glomerulonephritis or hyaluronidase Schistocytes on peripheral smear, decreased Hemolytic uremic syndrome or thrombotic haptoglobin level, elevated lactate dehydrogenase thrombocytopenic purpura level or elevated serum bilirubin level Low albumin level

Liver disease or nephrotic syndrome

Modified from Agrawal and Swartz, 2000

On the basis of laboratory studies, the urinary sediment helps to distinguish whether serious renal disease is present (Table 2) (Agrawal and Swartz, 2000). The presence of active urinary sediment suggests a glomerular or interstitial inflammatory immune response and greater likelihood of an associated reduction in renal function. In addition, serological tests for hepatitis (both B and C), HIV, and syphilis may be helpful (Wingo and Clapp, 2000).

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With new early markers for renal injury such as NGAL (neutrophil gelatinase-associated lipocalin or lipocalin-2), physicians can initiate proper management of acute renal failure within hours rather than days of the insult. The lack of an early diagnostic marker for acute renal failure has held back improvements in treatment methods (Miklaszewska et al., 2006; Trachtman et al., 2006). High serum creatinine concentrations were defined by a cutoff value of ≥115 umol/L in women and ≥133 umol/L in men based upon prior studies. A creatinine level of 120 to 150 umol /L represents a loss of filtration function of more than 50%. Early referral for such cases will avoid irreversible renal disease to occur (Mendelssohn et al, 1999). Heavy proteinuria generally reflects the presence of significant glomerular pathology and nephrotic syndrome. ‘Nephrotic range’ proteinuria (>3.0g/24h) is always glomerular in the absence of urinary infection. Proteinuria is also an important prognostic indicator for the progression of chronic renal damage (EdRen Handbook, 2007). Nephrotic syndrome leads to hypoalbuminemia, edema, and hyperlipidemia that in turn result in diverse complications, such as increased thromboembolic events, renal tubular dysfunction, and increased susceptibility to infections (Wingo and Clapp, 2000). When considering persons with nephrotic-range proteinuria, it is useful to determine whether the proteinuria is present in association with active urinary sediment (containing cells and/or casts) or whether it reflects isolated proteinuria. If there is active urinary sediment, one is usually either dealing with a primary glomerulonephritis or a glomerulonephritis secondary to a systemic disease. The most likely systemic diseases that produce proteinuria with an active, or nephritic, urinary sediment are SLE, vasculitis, endocarditis, and cryoglobulinemia (Wingo and Clapp, 2000)

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TABLE 2 Findings on Urinalysis in the Broad Categories of Acute Kidney Injury Type of renal failure

Findings on urinalysis

Prerenal acute renal failure Postrenal acute renal failure Acute tubular necrosis

Scant; few hyaline casts

Allergic interstitial nephritis Glomerulonephritis

Scant; few hyaline casts, possible red cells Epithelial cells, muddy-brown, coarsely granular casts, white blood cells, low-grade proteinuria White blood cells, red blood cells, epithelial cells, eosinophils, possible white blood cell cast, low to moderate proteinuria Red blood cell casts, dysmorphic red cells, moderate to severe proteinuria

Adapted from Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448-60.

If this patient has nephrotic range proteinuria but the examination of the urinary sediment is largely unremarkable, one should consider certain systemic diseases as a possible cause. The most common of these is diabetic nephropathy and a careful examination for diabetic retinopathy may lead to a presumptive diagnosis (because of the age this is unlikely). SLE may occasionally present with a secondary membranous glomerulonephritis and isolated proteinuria. Serologic testing may support the diagnosis before overt clinical symptoms of SLE are present. Although nephrotic-range isolated proteinuria is rarely observed in uncomplicated hypertension, it may be seen in malignant hypertension. The presence of hypertension and proteinuria, particularly if associated with renal insufficiency with unremarkable urinary sediment, should lead one to test for the presence of lead and other heavy metal toxicity. Also, plasma cell dyscrasias and amyloidosis may present with isolated nephrotic-range proteinuria. If these secondary causes of isolated nephrotic-range proteinuria are excluded, then the likely cause of the proteinuria is a primary glomerular disease; membranous glomerulonephritis, focal segmental glomerulosclerosis, or minimal change disease (also called lipoid nephrosis) are the most likely 13    

causes. IgA nephropathy may present with nephrotic-range proteinuria, although hematuria is a more common form of presentation. The diagnosis of these conditions usually should be confirmed by renal biopsy (Wingo and Clapp, 2000).

Acute kidney injury (AKI) is frequently defined as an acute increase of the serum creatinine level from baseline (i.e., an increase of at least 0.5 mg per dL [44.2 µmol per L]) or a 50 % increase in the creatinine level above the baseline value, a 50 % decrease in the baselinecalculated glomerular filtration rate (GFR) (Singri et al., 2003). This finding is matching with the laboratory result of this case which suggesting a case of acute kidney injury. Using a step-by-step clinical approach, physicians can determine the cause of acute kidney injury in most patients (Figure 1).

Acute kidney injury pathophysiologic changes are categorized into; Pre-renal, intrinsic and postrenal. 1. Prerenal represents 60 to 70 % of the cases. It is characterized by hypoperfusion of the kidney without compromise of the integrity of the renal parenchyma

a. Hypovolemic – Hemorrhage, vomiting, diarrhea, burns, surgical drains, diuresis (drugs, osmotic), third spacing (eg/ pancreatitis, hypoalbuminemia) c. Decreased ECV – CHF, nephrotic syndrome, hepatorenal d. Systemic vasodilatation – Sepsis, anaphylaxis, antihypertensives e. Drugs – ACE inhibitors, NSAIDS, radiocontrast 2. Renal AKI represents 25 % of the cases. It is directly affects renal parenchyma. Further categorized into vascular, glomerular, tubular, and tubulointerstitial. a. Vascular i.Macrovascular – Renal artery stenosis, thromboembolism, atherosclerotic plaque, dissection, renal vein thrombosis ii.Microvascular – Hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), HELLP

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b. Glomerular – RPGN, Wegener’s granulomatosis, Goodpasture’s syndrome, microscopic polyangiitis, postinfectious GN, membranous nephropathy, lupus nephritis, Henoch-Schölein purpura c. Tubular/ATN i.Ischemia – Surgery, hemorrhage, arterial or venous obstruction, ACEI, NSAIDs, radiocontrast, amphotericin B ii.Exogenous toxins – Radiocontrast, aminoglycosides, β-lactam antibiotics, amphotericin B, cyclosporine, sulfonamides, heavy metals, methotrexate iii.Endogenous toxins – Rhabdomyolysis, hemoglobinuria, myoglobinuria, uric acid crystals, myeloma protein, hypercalcemia d. Interstitial i.Allergic interstitial nephritis – NSAIDS, β-lactam antibiotics, sulfonamides, ciprofloxacin, thiazide diuretics, allopurinol ii.Infection – Acute pyelonephritis iii.Infiltration – Sarcoid, Lymphoma 3. Postrenal AKI represents 5% of the cases. It is associated with urinary tract obstruction – BPH, bladder cancer, renal calculi, retroperitoneal fibrosis and urethral stricture or valves. (Needham, 2006; Agrawal and Swartz, 2000; Brady and Singer, 1995). By interpenetrating the laboratory results for this patient, it can be concluded that the case is acute kidney injury. Considering the IV drug abuse is a causative factor for AKI due to renal effect. Heavy asymptomatic proteinuria associated with presence of oedema suggested nephrotic syndrome or a glomerular disorder, caused either by a primary renal disease or renal involvement as a result of systemic disease.

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Acute Kidney Injury

FIGURE 1. Algorithm for the diagnosis and treatment of acute renal failure. (HELLP = hemolysis, elevated liver enzymes and low platelets.) Modified from Agrawal and Swartz, 2000

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Chapter III Differential Diagnosis The diagnosis of this case is highlighted by the obvious acute renal system involvement, the indicators are; the elevation in serum creatinine level and heavy and persistent proteinuria. Patients with asymptomatic proteinuria usually have no signs, but in more severe cases, such as with nephrotic syndrome, there may be oedema, ascites , hydrocoeles and pleural effusions as a result of decreased oncotic pressure. Nephrotic syndrome consists of proteinuria, hypoalbuminaemia, hyperlipidemia and oedema. Moreover an elevated serum creatinine level can be acute or chronic. An acute rise in the serum creatinine level (during a period of hours or days) has been called acute renal failure. This term has been replaced by acute kidney injury, defined as either an absolute increase in the serum creatinine level of more than 0.3 mg per deciliter (26.5 μmol per liter) or a percentage increase of more than 50% (by a factor of 1.5 from baseline) (Rabb and Colvin., 2007). Table 3 shows the diagnostic marker for AKI.

TABLE 3 Diagnostic Indices in Acute Kidney Injury

Index

Postrenal

Tubular Injury

AGN

Prerenal

U/P osmolality

> 1.5

1 to 1.5

1 to 1.5

1 to 1.5

Urine Na (mmol/L)

< 20

> 40

> 40

> 30

< 0.01

> 0.04

> 0.02

< 0.01

<1

>2

>2

<1

Fractional excretion of Na (FENa)* Renal failure index

*U/P Na ÷ U/P creatinine, †Urine Na ÷ U/P creatinine ratio, AGN = acute glomerulonephritis; U/P = urine-to-plasma ratio. Adapted from Miller TR, et al: “Urinary diagnostic indices in acute renal failure.” Annals of Internal Medicine 89(1):47–50, 1978.

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Causes of acute kidney injury are divided into prerenal, intrarenal, and postrenal factors (Table 4) (Rabb and Colvin., 2007).

TABLE 4 Differential Diagnosis of Acute Kidney Injury Types of acute renal failure and underlying Possible disorders problem Prerenal acute kidney injury

True intravascular depletion Decreased effective circulating volume to the kidneys Impaired renal blood flow because of exogenous agents

Sepsis, hemorrhage, overdiuresis, poor fluid intake, vomiting, diarrhea Congestive heart failure, cirrhosis or hepatorenal syndrome, nephrotic syndrome Angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs

Intrinsic AKI

Acute tubular necrosis Ischemia Toxins: drugs (e.g., aminoglycosides), contrast agents, pigments (myoglobin or hemoglobin) Rapidly progressive glomerulonephritis: systemic lupus erythematosus, smallGlomerular disease vessel vasculitis (Wegener's granulomatosis or polyarteritis nodosa), HenochSchönlein purpura (immunoglobulin A nephropathy), Goodpasture's syndrome Acute proliferative glomerulonephritis: endocarditis, poststreptococcal infection, postpneumococcal infection Vascular disease

Interstitial disease

Postrenal AKI

Microvascular disease: atheroembolic disease (cholesterol-plaque microembolism), thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, HELLP syndrome or postpartum acute renal failure Macrovascular disease: renal artery occlusion, severe abdominal aortic disease (aneurysm) Allergic reaction to drugs, autoimmune disease: (systemic lupus erythematosus or mixed connective tissue disease), pyelonephritis, infiltrative disease (lymphoma or leukemia) Benign prostatic hypertrophy or prostate cancer, cervical cancer, retroperitoneal disorders, intratubular obstruction (crystals or myeloma light chains), pelvic mass or invasive pelvic malignancy, intraluminal bladder mass (clot, tumor or fungus ball), neurogenic bladder, urethral strictures

HELLP = hemolysis, elevated liver enzymes, and low platelets. Modified from Friedewald and Rabb 2007.

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The differential diagnosis of this patient‘s impaired kidney function, based upon reviewing the related-literatures, possibly are: acute kidney injury due to rhabdomyolysis or acute tubular necrosis, nephrotic syndrome, glomerulonephritis (GN) induced by Staphylococcus aureus from unsterile injection, endocarditis due to bacterial and fungal infection, membranous nephropathy due to hepatitis B infection, mesangiocapillary GN due to hepatitis C infection, secondary (AA) amylodosis due to prolonged parenteral drug use (Miranda et al., 2006), heroin-associated nephropathy (HAN), or HIV-associated nephropathy (HIVAN).

Literature review regarding the different diagnostic possibilities. The renal complications of drug abuse are also becoming more frequent, and may encompass a spectrum of glomerular, interstitial and vascular diseases. Although some substances are directly nephrotoxic, a number of other mechanisms are also involved. These effects are often chronic and irreversible, but occasionally acute with possible recovery (Crowe et al., 2000). There are several renal complications from heroin abuse. Coma from overdose or underestimated drug potency leads to pressure induced muscle damage and rhabdomyolysis. Hypotension, hypoxia, acidosis and dehydration may aggravate this. Others have demonstrated rhabdomyolysis in the absence of coma or evidence of muscle compression, and suggest this could be due to a direct toxic effect or an allergic response to heroin or the components in impure heroin (Grossman et al., 1974). Follow-up studies of heroin addicts indicate an annual mortality of 4.8% (Gunne and Gronbladh, 1981). The majority of these drugs, or their metabolites, are excreted via the kidney. To achieve their recreational effects these drugs must cross the blood-brain barrier and many are highly lipid-soluble; this results in high volumes of distribution with dialysis of little benefit in overdose (Crowe et al., 2000). European Renal Association study for 156 heroin addict patients along a period of 23 months showed that l5.5% of them had renal disease. In first group of patient, kidney biopsies 19    

showed the presence of proliferative glomerulonephritis (GN), diffuse and focal proliferative GN associated to Staphylococcus aureus endocarditis or sepsis. Clinical presentation included proteinunia, frequently in a nephrotic range, microscopic hematuria and hypocomplementamia. Diffuse forms showed no histological differences with the post streptococcal acute GN. Heroin nephropathy detected among three patients. Two of them showed a focal and segmental qlomerulosclerosis and the third case had a membranoproliferetive GN. Nephrotic syndrome was the most frequent presentation form and one of the focal and segmental glomeruloselerosis patients showed a complete remission after cessation in heroin addiction. Furthermore, acute tubular necrosis because of sepsis or nephrotoxic drugs, along or acompanning to the previous lesions, was found in 11 cases. This patients had and oliguric acute renal failure and 10 of' them dead. Ten patients had serum virus 3 markers but only one of them had positive anti HBsAg glomerular deposits. It was concluded that heroin addiction is increasing in an important risk of renal disease. Different histological findings are present in relation to heroin toxicity, its vehicles and contaminants or more frequently to sepsis. The heroin nephropathy can improve after discontinuation of' drug addiction. The association to acute renal failure is frequent end has a high mortality rate (Lopez-Gomez el al., 1985). There is a high rate of viral, bacterial and fungal contamination associated with intravenous drug misuse, including heroin (Tuazon et al., 1974), and consequently users are at risk of a variety of infections. Glomerulonephritis (GN) may be associated with these chronic infections. Local pyogenic abscesses, due to Staphylococcus aureus, have been associated with GN, thought to be due to deposition of immune complexes formed in response to the organism. Bacterial and fungal (Roberts and Rabson, 1975) endocarditis can also cause immune-complexmediated GN(Stein, 1990). Hepatitis B has also been associated with GN, usually membranous and with polyarteritis nodosa. Hepatitis C causes mesangiocapillary GN with associated cryoglobulinaemia. Secondary (AA) amyloidosis has increased in frequency as a cause of renal disease in chronic parenteral drug users (Crowe et al., 2000). In the 1970s and 1980s, heroin-associated nephropathy (HAN) was described, presenting as nephrotic syndrome and progressing rapidly to end-stage renal failure. Occasionally the process reversed with discipline from further heroin use. Renal biopsy usually showed a focal segmental glomerulosclerosis. The pathogenesis of this is unclear; earlier studies suggested that 20    

heroin, or one of its adulterants, acted as antigen leading to renal deposition of immune complexes in the kidney (Sreepada Rao et al., 1977). More recent animal studies have shown that morphine may a direct effect on the glomerulus, causing proliferation of fibroblasts and a decrease in degradation of type IV collagen (Crowe et al., 2000). Nowadays, HIV-associated nephropathy (HIVAN) is being diagnosed more frequently among heroin addicts with HIV infection (D’Agati et al., 1998). HIVAN also presents with nephrotic syndrome and rapidly progressing renal failure, and it can cause up 38% of end-stage renal failure (Pastan et al., 1998). Renal biopsy usually reveals characteristic collapsing glomerular tuft with epithelial cell prominence. Localized segmental sclerosis of the tuft can also occur (Humphreys, 1995). A recent report of a case of clinical and histological resolution of HIVAN following treatment with triple antiretroviral therapy and reduction in viral load supports the hypothesis that the virus has a direct cytopathic effect on the kidney (Wali et al., 1998). A wide spectrum of renal complications can occur with both acute and chronic use of cocaine. Except for cocaine-induced rhabdomyolysis, the direct effects of cocaine on the kidney have received less attention. The pathophysiologic basis of cocaine-related renal injury is multifactorial and involves changes in renal hemodynamics, changes in glomerular matrix synthesis, degradation and oxidative stress, and induction of renal atherogenesis (Jaffe and Kimmel, 2006). Acute renal failure can occur as a result of rhabdomyolysis (Roth et al., 1988). In one series 24% of patients seen in an emergency department with cocaine-associated complaints presented with concentrations of creatine kinase of more than 1000U/l.20 (Welch et al., 1991). Up to one third of such patients develop acute renal failure (Roth et al., 1988). Muscle ischaemia caused through prolonged vasoconstriction of intramuscular arteries, generalized seizures, coma with secondary muscle compression, or direct myofibrillar damage are different mechanisms of cocaine-induced rhabdomyolysis. Cocaine may be contaminated with arsenic, strychnine, amphetamine and phencyclidine, which may also cause seizures and

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rhabdomyolysis (Cregler and Mark, 1986). Moreover, a case of cardiorespiratory arrest was reported after cocaine and heroin ingestion. The arrest is attributed primarily to hyperkalaemia/ rhabdomyolysis, a recognized consequence of each of these drugs (McCann et al., 2002). The syndrome of cocaine-induced premature artery disease is well described. Less well known is that cocaine can cause renal infarction (Sharff, 1984) and atherosclerosis of the kidney (Fogo

et al., 1992)(Di Paolo et al., 1997). However, a recent study of 301 chronic cocaine users

showed no association with chronic hypertension or the development of microalbuminuria (Brecklin et al., 1998). There may be perhaps a propensity for cocaine to exacerbate pre-existing renal disease rather than cause de novo disease (Dunea et al., 1995). Immunologically, cocaine has been shown to cause mesangial proliferation by increasing the release of interleukin-6 by macrophages, which may be a cause of focal segmental glomerulosclerosis. Associations of cocaine abuse with renal scleroderma (Lam and Ballou, 1992) and Henoch-Schönlein purpura have also been described (Chevalier et al., 1995). In experimental animals, MDMA (3,4-methylenedioxymethamphetamine) has been shown to cause fever even in the absence of strenuous exercise. Unwanted effects may be minor loss of appetite nausea, vomiting, headaches, trismus and cramps, or serious convulsions, hyperpyrexia, hepatic dysfunction, rhabdomyolysis, disseminated intravascular coagulation (Henry et al., 1992) and acute renal failure. (Fahal et al., 1992) The patient with rhabdomyolysis typically presents with muscle pain and tenderness, and is found to be in acute nephrotoxic renal failure with hyperkalaemia, hyperphosphataemia, and raised creatine kinase. Myoglobin and granular casts are found in the urine. Approximately 70% of injecting drug users has used temazepam at sometime. (Lavelle et al., 1991). Acute renal failure has been described following inadvertent intraarterial temazepam injection. This provokes limb ischaemia as a result of particulate embolization and subsequent rhabdomolysis and myoglobinuria.(Blair et al., 1991) Severe but temporary dialysis-dependent renal failure was present in 20% of patients in one series (Jenkinson and Pusey ,1994) (Crowe et al., 2000). 22    

Deighan et al., 2000 reported, in retrospective review of dialysis-dependent ARF between 1986–1997, an increase in ARF and non-traumatic rhabdomyolysis associated with drug abuse in West of Scotland. The incidence of dialysis dependent AKI from rhabdomyolysis due to drug abuse over a period of 12 years 1986-1991 has increased markedly from 17 cases to 59 cases in the next 6 years. The increase in rhabdomyolysis and acute renal failure is likely to be due to the increased parenteral abuse of drugs such as temazepam. First reports of intravenous abuse of temazepam came from Glasgow in 1987 (Stark et al., 1987). In November 1989 the formulation of temazepam was changed to a hard gel in an attempt to discourage misuse. Addicts however circumvented this problem by heating the `jellies' on a metal spoon and then injecting the melted substance into an accessible blood vessel. Subsequently a number of reports of ischaemic limbs after intra-arterial injection of temazepam were published (Blair et al., 1991; Scott et al., 1992) and in 1994 Jenkinson and Pusey reported two cases of rhabdomyolysis and acute renal failure following intra-arterial injection of temazepam. All 13 cases reported here occurred after the change in formulation of the temazepam and this change appears to have contributed to the increased incidence of acute renal failure from rhabdomyolysis. The increased longevity of drug users leads to the emergence of new diseases as a result of chronic bacterial and viral infection. It was reported that secondary AA amyloidosis is a serious complication of chronic soft tissue infection in intravenous drug users in central London. Affected individuals invariably presented with nephritic range proteinuria (mean 7.3 g/l, range 0.5–14.8 g/l) and advanced renal failure. A high proportion of patients (85%) had a history of recurrent deep-vein thrombosis. The reporter speculated that the increasing drug longevity in users with poor venous access, and the attendant increase in subcutaneous injection and sepsis, is a major contributory factor in the development of amyloidosis (Connolly et al., 2006). In summary, a variety of renal diseases may result from the repeated injection of drugs with the apparently contaminated paraphernalia which drug addicts utilize. First is the focal or diffuse glomerulonephritis which develops in patients with bacterial endocarditis. Next is the 23    

lesion associated with acute viral hepatitis, characterized by proteinuria of less than 2 gm/day and focal increase in PAS-positive material in the mesangium. Renal involvement with necrotizing angiitis has also been reported. Another group of these patients may present with acute renal failure secondary to myoglobinuria due to muscle injury at the site of self-injection of water which is apparently used during withdrawal. Finally, nephritic syndrome of no apparent etiology is gradually becoming recognized as occurring in greater frequency in the drug addict (Eknoyan, 1975).

Management of acute Kidney Injury Management of established acute kidney injury involves general measures (Table 5) irrespective of the cause and specific treatments targeted to the particular cause. The goal of treatment is to restore kidney function and prevent fluid and waste from building up

TABLE 5 Supportive therapies for renal dysfunction • •

in the body while the kidneys recover. Initial treatment

should focus on correcting fluid and electrolyte balances and uremia, provide nutritional support, and prevent or treat complications such as infection (Hilton, 2006). Since impaired kidney function in this case is associated with IV drug abuse. Cessation of nephrotoxins uptake is one of the main supportive

• •

Sodium and water prescriptions. Blood pressure control with ACE inhibitors, angiotensin receptor blockers. Avoidance of nephrotoxins especially drugs, such as NSAIDs, contrast agents. Smoking avoidance, low-protein diet (benefit controversial, but not harmful).

Adapted from Cunard R and Kelly CJ. Immune-mediated renal disease. J Allergy Clin Immunol 2003;111:S637-44.

approaches.

Because acute renal failure is a catabolic state, patients can become nutritionally deficient. Total caloric intake should be 30 to 45 kcal (126 to 189 kJ) per kg per day, most of which should come from a combination of carbohydrates and lipids. In patients who are not receiving dialysis, protein intake should be restricted to 0.6 g per kg per day. Patients who are receiving dialysis

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should have a protein intake of 1 to 1.5 g per kg per day (Wolfson and Kopple, 1993) (Agrawal and Swartz, 2000). In spite of much research, no drug treatment has as yet been shown to limit the progression of, or speed up recovery from, acute renal failure, and some drugs may be harmful (Kellum et al., 2001) (Hilton, 2006). The use of furosemide warrants particular mention, as this is a commonly used and inexpensive intervention. A recent meta-analysis of randomised controlled trials showed that furosemide is ineffective in preventing and treating acute renal failure and that high dose may be associated with ototoxicity (Kwok and Sheridan, 2006). Note that there is no evidence that dopamine is of benefit. There are some reasons to suspect that it may be potentially harmful as it impairs splanchnic perfusion. Loop diuretics may increase urine output in those with less severe degrees of renal failure, but there is no evidence that they improve outcome (requirement for or duration of dialysis, or mortality) and some evidence that they can be harmful. Most interventions tested in prevention of ARF after radiographic contrast administration is ineffective or harmful (e.g. loop diuretics), apart from fluid administration alone: and N-acetylcysteine may at least do no harm.

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Chapter IV Discussion: Acute kidney injury due to intravenous drug abuse may be reversible. Managing this case would be based on the different diagnosis listed above. Firstly, treatment via controlling critical measures which include maintaining adequate intravascular volume and mean arterial pressure, discontinuing all nephrotoxic drugs, and eliminating exposure to any other nephrotoxins, secondly by specific medications according to the diagnosis which either HAN, HIVAN or postinfectious glomerulonephritis. Many medications can injure the kidneys therefore dosing schedules (i.e. a once-daily dose is preferable than multiple daily doses) can help prevent acute renal failure. A combination of ACE inhibitors and a loop diuretic ( e.g furosemide) will be sufficient to control proteinurea and peripheral oedema. If the case is not responding to treatment addition of thiazide diuretic (e.g., metolazone) will be required. Patients receiving this agent need to be monitored for K+ level. The literatures mentioned variety of specific treatment for each possible differential diagnosis discussed below as following:

Heroin-associated nephropathy (HAN) Naloxone is an effective opioid antidote but it is not without harmful side effects. Naloxone may be harmful for two reasons: (1) administration of naloxone with combined opioid and sympathomimetic intoxication may provoke life threatening manifestations of sympathomimetic toxicity by removing the protective opioid mediated CNS depressant effects (Hung et., al 1998) (2) the risk of arrhythmia as arrhythmogenesis of naloxone is well documented and the risk may increased in this case on the background of hyperkalaemia. Therefore establishing the timing of ingestion of narcotics in relation to the time of presentation is very crucial (McCann et al., 2002).

HIV-associated nephropathy (HIVAN) Patients with biopsy-proven HIVAN treated with Antiretroviral therapy (ART) had better renal survival compared with patients who did not receive ART. HIVAN should be considered as an indication to initiate ART (Atta et al., 2006)

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Focal segmental glomerulosclerosis Treatment is generally recommended for nephrotic patients (Korbet et al 1998) Current protocols recommend treating with prednisone 1 mg/kg/d for 3 to 4 months. As with other nephroses, angiotensin-converting enzyme (ACE) inhibitors reduce proteinuria and are renoprotective (Savin et al., 1996).

Amyloidosis The prognosis of patients with amyloidosis is poor and therapy with melphalan and prednisone are recommended. In patients with AA amyloidosis, treatment should be focused on resolving the chronic inflammatory state. Colchicine has been effective in treating amyloidosis, in particular, in familiar Mediterranean fever (Livneh et al.,2001). Treatment options of secondary (AA) amylodosis due to chronic parenteral drug use are limited and the outcome for such patients on renal replacement was poor. Arresting the progression of systemic amyloidosis depends on reducing inflammation and SAA precursor protein production by treating the underlying condition. Spontaneous resolution and successful treatment with colchicine of renal amyloidosis has been reported in intravenous drug users, which supports the idea that removal of the inflammatory stimulus, usually chronic skin sepsis, can lead to reversal of the disease (Connolly et al., 2006).

Postinfectious glomerulonephritis However, in some adults the disease can be more chronic. Antibiotics and supportive therapy are recommended. Increasingly other bacteria, such as staphylococci and gram-negative rods, are implicated in causing postinfectious GN. The pathogenesis is presumed to also be secondary to ICs. Alcoholics, diabetics, and intravenous drug users are most commonly affected (Montseny et al., 1995).

Mesangiocapillary GN due to hepatitis C infection Gold therapy has been associated most commonly with membranous nephropathy (MN); however, MCNS and mesangial GN have been reported. Proteinuria has also been observed in 7% to 18% of patients treated with D-penicillamine. Proteinuria classically begins after 6 to 12 27    

months of therapy with these antirheumatic agents. The proteinuria is generally reversible but can take over a year to abate after drug withdrawal (Schiff and Whelton, 2000). Cyclosporine causes renal afferent arteriolar constriction, and biopsies reveal focal interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis. Toxicity is related to the doses used (≥5 mg/kg/d), age of patients (> 65 years of age) and degree of underlying kidney disease. It is recommended to follow renal function closely, especially in the elderly, and to avoid combination therapy with NSAIDs. Methotrexate rarely causes renal toxicity; however, it is excreted by the kidney and can accumulatein patients with renal insufficiency (Cush et al., 1999).

Membranoproliferative GN The secondary MPGN most commonly to be associated with hepatitis C infection in the majority of cases (Johnson et al., 1993; Rennke, 1995). Monoclonal IgM, possessing rheumatoid factor activity, is a cryoglobulin. The pathogenesis of the renal diseases is either related to deposition of circulating ICs with attendant complement activation, or the monoclonal IgM may additionally recognize endogenous glomerular proteins. The disease is a systemic vasculitis, with the renal involvement typically demonstrating proteinuria, hematuria, renal insufficiency, and hypertension. The efficacy of interferon-α and ribavirin for hepatitis C–related renal disease has yet to be defined, but it is being used. Ribavirin should not be used with creatinine clearance less than 50 mL/min. Long-term treatment with antiplatelet agents may slow progression of the disease in adults (Zauner etal., 1994).

Nephrotic syndrome: The goals of treatment are to relieve symptoms, prevent complications and delay progressive kidney damage. Treatment of the causative disorder is necessary to control nephrotic syndrome. Treatment may be required for life. Corticosteroid, immunosuppressive, antihypertensive, and diuretic medications may help control symptoms. Antibiotics may be needed to control infections. Angiotensin converting enzyme (ACE) inhibitors may significantly reduce the degree of protein loss in the urine and are therefore frequently prescribed for treatment of nephrotic syndrome.

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If hypertension occurs, it must be treated vigorously. Treatment of high blood cholesterol and triglyceride levels is also recommended to reduce the risk of atherosclerosis. Dietary limitation of cholesterol and saturated fats may be of little benefit, as the high levels which accompany this condition seem to be the result of overproduction by the liver rather than from excessive fat intake. Medications to reduce cholesterol and triglycerides may be recommended. High-protein diets are of debatable value. In many patients, reducing the amount of protein in the diet produces a decrease in urine protein. In most cases, a moderate-protein diet (1 gram of protein per kilogram of body weight per day) is usually recommended. Sodium (salt) may be restricted to help control swelling. Vitamin D may need to be replaced if nephrotic syndrome is chronic and unresponsive to therapy. Blood thinners may be required to treat or prevent clot formation (Mushnick, 2005)

Conclusion In conclusion, the diagnosis of this patient likely is intra-renal acute kidney injury, supported by the patient biochemical report which showed proteinuria, high serum creatinine. Initially, the patient needs supportive treatment. Therefore the first line of treatment for this patient is a symptomatic. In addition dietary treatment consisted of restricted dietary of salt, protein and fluid. The combination of a loop diuretic ( e.g furosemide) with thiazide diuretic ( e.g., metolazone) has additive effects and can be used to the patients who are not responding to loop diuretics alone. If the K+ level decreased, supplementation of potassium or addition of potassium sparing diuretics (amiloride or spironolactone) may be nessesary (Willcox and Tisher, 2005). ACE inhibitor can be used to reduce proteinuria (longmore et al., 2004). Considering that ACE inhibitor can cause hyperkalemia so need to monitor K+ level. For long term treatment this patient need to admitted to rehabilitation centre to recover from drug addiction.

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